Composition Comprising Methylphenidate and Another Drug

ABSTRACT

A process of treating a subject that is undergoing methylphenidate therapy and concomitant therapy with another drug undergoes or interferes with P 450  metabolism wherein the methylphenidate is d-threo-methylphenidate.

FIELD OF THE INVENTION

This invention relates to a new composition comprising methylphenidateand another drug, and also to new ways of using known drugs includingd-threo-methylphenidate (abbreviated herein as dtmp).

BACKGROUND OF THE INVENTION

Methylphenidate is a known drug (although it is a controlled substance)It is used primarily to treat hyperactive children.

Methylphenidate is a chiral molecule. The properties of the enantiomershave been investigated to some extent, although the drug is stilladministered as the racemate. It is generally thought that dtmp is theactive material, and that its antipode (ltmp) is metabolised morerapidly.

Methylphenidate is often administered in conjunction with other drugs.It is known that the concurrent administration of two drugs that act orare metabolised through the same metabolic pathway can block thatpathway, leading to drug interaction.

Racemic methylphenidate is known to interact clinically with a varietyor drugs, such as the tricyclic antidepressants (TCAs), necessitatingreduction in the TCA dosage when co-administered to prevent druginteraction (Physicians Desk Reference, Guide to Drug Interactions,1994).

It is generally believed that the separate enantiomers of chiraltherapeutic drugs exhibit different toxicological profiles, with oneusually being the main cause of the toxic effects of drug interactions;see Ariens, Schweiz. Med. Wochenschr. 120(5) 131-134 (1990). The basisfor this is that each enantiomer will exhibit different preferences forthe pathways of enzyme metabolism, e,g. the cytochrome P₄₅₀ pathways,and therefore co-administered drugs are blocked at different sites ofmetabolism.

SUMMARY OF THE INVENTION

It has been discovered that, surprisingly, both dtmp and ltmp similarlyinhibit metabolism of other drugs by the cytochrome P₄₅₀ systems, inhuman microsomes. Further, the racemate is shown to have a greaterinhibitory profile than either of the enantiomers, suggesting aninteraction between the two. Administration of dtmp, substantially freeof ltmp, will substantially reduce the inhibition of P₄₅₀ isczymes. Thishas beneficial effects for patients undergoing concurrent administrationof other drugs. To avoid the resultant risk of drug-drug toxicity, thepresent invention involves the administration of that other drug anddtmp. The two drugs used in this invention may be administeredsequentially, concurrently or simultaneously, by the same or separatemeans.

The discovery is based on data showing that, surprisingly, dtmpadministration results in less toxicity in the mouse liver than racemicmethylphenidate, possibly due to less inhibition of hepatic cytochromeP₄₅₀ enzymes. The experiments and data are summarised below. Theinvention is thus of particular utility in that proportion of thepopulation in which the relevant enzymes have reduced efficiency, orthat are receiving the cross-reacting drugs, e.g. SSRIs, in therapy of,say, anxiety or depression.

DESCRIPTION OF THE INVENTION

The dtmp that is used in this invention is substantially free of ltmp,e.g. in an enantiomeric excess (ee) of at least 70%, preferably at least90%, and more preferably at least 95%. The dtmp may be substantiallyenantiopure. It may be used in the form of any suitable salt, e.g. thehydrochloride.

As indicated above, the dtmp and other drug may each be administeredindependently. The invention is not restricted to any particular routeof administration, and it will be generally preferred that therespective drugs are administered by their preferred routes. Thus, thedtmp may be administered by the same means as racemic methylphenidate,e.g. in a sustained-release formulation, e.g. a coated tablet. Morepreferably, the formulation is as described in the copending PatentApplication entitled “Sustained-Release Formulation of Methylphenidate”,filed on the same date, also assigned to Chiroscience Limited, andclaiming priority from British Patent Application No. 9514451.5. Therelevant content of that Application is incorporated herein byreference. Advantages of the use of dtmp are also described therein, andmay include linear kinetics within the clinically relevant dose range,the reduction of exposure to a controlled substance, reducedside-effects (which include anorexia, insomnia, stomach ache andheadache), reduced hepatotoxicity, reduced abuse potential, reducedC_(max), a reduced level of active material even when chewed, reducedpatient variability, and less variability between fed and fastedsubjects.

By controlling the nature of the formulation, it is possible to controldissolution in vitro, and thus match or exceed the US National Formulary(NF) drug release profile for methylphenidate hydrochloride. Further,when administered to a healthy subject, a serum level of dtmp can beattained that is at least 50t of C_(max), over a period of at least 8hours, e.g. 8-16, 8-12 or 8-10 hours. Thus, for example, a shorterrelease period may be preferred or a different period before the serumlevel drops below a different proportion of C_(max).

The serum level may be also controlled so that it remains high duringthe day, after taking a dosage in the morning, and is reduced in theevening, before it can have any undesirable effect on sleeping patterns.

A formulation of the invention may be a unit dosage such as a tablet,capsule or suspension. A sustained-release formulation may be in matrix,coating, reservoir, osmotic, ion-exchange or density exchange form. Itmay comprise a soluble polymer coating which is dissolved or eroded,after administration. Alternatively, there may be an insoluble coating,e.g. of a polymer, through which the active ingredient permeates, asfrom a reservoir, diffuses, e.g. through a porous matrix, or undergoesosmotic exchange. A further option for a sustained-release formulationinvolves density exchange, e.g. in the case where the formulation alterson administration, e.g. from microparticles to a gel, so that the activeingredient diffuses or permeates out. Ion-based resins may also be used,the active component being released by ionic exchange, and wherein therate of release can be controlled by using cationic or anionic forms ofthe drug.

It is preferred to use a formulation in this invention that is resistantto chewing, e.g. micronised particles that are individually coated andwhich do not immediately release the active component on chewing, orpossibly even actively discourage chewing by their consistency.Formulations of the invention that provide improved releasecharacteristics may also be appropriate for the administration ofracemic methylphenidate. Further, many effects, benefits etc. describedherein apply to formulations providing immediate release. The variouseffects etc may be due to the use of dtmp and/or the absence of ltmp.

The other drug may be administered in admixture with themethylphenidate. Alternatively, it may be administered in any otherformulation, via any suitable route of administration. Conventionaldosing parameters may be adopted, i.e. those which are known to oradapted to the practice of those skilled in the art. For example, thedaily dosage of dtmp may be 5 to 60 mg, but will be chosen according tothe age, weight and health of the subject, and other factors that areroutinely considered by the man skilled in the art.

The dtmp may be administered for its primary utility, i.e. treatinghyperactive children, as a stimulant in cancer patients treated withnarcotic analgesics, or for treating depression (e.g. in AIDS patients),compulsive shopping disorder, narcolepsy or hypersomnia. These subject&typically suffer other complaints requiring medication. The presentinvention is particularly adapted to the use of such other drugs, e.g.agents that are adapted to treat CNS disorders (e.g. depression); suchagents may be tricyclic antidepressants or SSRIs. Thus, the other drugmay be one that has the same mode of action, or which has a similar CNSactivity. Alternatively or in addition, the other drug that is used inthe invention may be any that undergoes the same metabolic degradationas ltmp, e.g. via the P₄₅₀ cytochromes, that interferes with ltmpmetabolism, or that has its metabolism interfered with by ltmp.

There are many drugs that may interact with methylphenidate. Examplesinclude anti-depressants.

Particular drugs of interest are those whose metabolism is known tooccur via the cytochrome P₄₅₀ pathways. For example, clomipramine,desipramine, indoramin, imipramine, phenformin and tropisetron undergoaromatic hydroxylation; amiflamine undergoes N-demethylation;amitriptyline and nortriptyline undergo benzylic hydroxylation; codeine,dextromethorphan, dihydrocodeine, hydrocodone, norcodeine and oxycodoneundergo o-demethylation; ethylmorphine undergoes O-de-ethylation;flecainide and methoxyamphetamine undergo O-dealkylation;methoxyphenamine undergoes aromatic hydroxylation and N-demethylation;mexiletine and ondansetron undergo hydroxylation; perhexiline undergoesaliphatic hydroxylation; and thioridazine undergoes side-chainsulfoxidation. These are merely examples of drugs that use the givenpathways. Other specific drugs of interest are cinnarizine, haloperidol,maprotiline, paroxetine and perphenazine.

Drugs of particular interest that have been seen to interact withmethylphenidate include tricyclic anti-depressants (TCAs) such asamitriptyline, amoxapine, clomipramine, desipramine, doxepin,imipramine, maprotiline, nortriptyline, protriptyline or trimipramine;monoamine oxidase inhibitors such as phenelzine, selegeline ortranylcypromine, selective serotonin reuptake inhibitors (SSRIs) such asfluoxetine, paroxetine or sertraline; antipsychotics such ashaloperidol; anticonvulsants/antiepileptics such as phenytoin, primidoneand diphenylhydantoin; anticoagulants such as warfarin; and other drugsfor which interactions have been reported such as isocarboxarid,metaramincl, phenylbutazone, phenylephrine, dopamide, norepinephrine,epinephrine, furazalidone, physostigmine and lithium.

It is often the case that a patient, typically a child, diagnosed ashaving attention-deficit hyperactivity disorder (ADHD; this term is usedherein to include also attention-deficit disorder), has concomitant CNSdisorders (whether or not diagnosed) which may require no immediatemedication but which indicate the likelihood of a future need for, say,a SSRI or TCA. The use of dtmp is indicated, according to thisinvention, for such a patient.

Adverse effects (including cognitive and mood deterioration) were seenin children treated with a combination of imipramine andmethylphenidate. Lithium significantly reduces the level ofarousal-activation, euphoria-grandiosity, and the total score ofmanic-state ratings following methylphenidate challenge.

Further, of 20 patients treated with tricyclics combined withmethylphenidate, 3 were withdrawn from the trial due to side-effects.These included dizziness, orthostatic blood pressure changes, dry mouth,increased anxiety and hypomania. Baclofen at 10 mg/kg produced a uniformblock of both methylphenidate-enhanced activity and stereotypics in ratswithin 15 to 25 minutes when administered 10 minutes followingmethylphenidate. Physostigmine and nethylphenidate each antagonised theeffects of the other in the treatment of manic patients.

Metabolism of Methylphenidate by Cytochrome P₄₅₀

Experiments were carried out to investigate the effect of racemicmethylphenidate, dtmp and ltmp on the hepatic cytochrome P₄₅₀ pathways.The experimental protocol utilised drugs known to be characteristicallymetabolised by a specific P₄₅₀ isotype, and measured the corresponding“enzyme activity” (see results Table, below) in human microsomepreparations, by standard methods; see:

-   Tolbutamide: Knodell et al, J. Pharmacol. Exp. Thes.    241(3):1012-1019 (1987);-   Mephenytoin: Yasumori et al, J. Pharmacol. Exp. Thes. 264(1) :89-94    (1993);-   Bufuralol: Kronbach et al, Anal. Biochem. 162:24-32 (1987); and-   Lauric Acid: Okita et al, Methods in Enzymology 206:432-441 (1991).

The involvement of the particular P₄₅₀ isotype was confirmed using knownstandard inhibitor compounds (see results Table), using the indicatedinhibitor concentrations. Methylphenidate, dtmp and ltmp were used at100 μM. Standard Inhibitor & % Inhibition of Enzyme Activity P₄₅₀ EnzymeConcentration Standard Racemic Isozyme Activity (μM) InhibitorMethylphenidate dtmp ltmp 2C9 Tolbutamide Sulpha- >90 19 25 34hydroxylase phenazole (100) 2C19 Mephenytoin Tranyl- 83 44 31 33hydroxylase cypronine (50) 2D6 Bufuralol Quinidine >90 65 64 41hydroxylase (10) 2B Lauric acid Disulfuram 47 <15 <20 <20 11- (10)hydroxylase

The results show that dtmp and ltmp have surprisingly similar profilesof inhibitory activity against the enzymes of the hepatic cytochromeP₄₅₀ pathway. Further, racemic methylphenidate appears more inhibitoryof certain enzymes than either dtmp or ltmp. A reduction in theinhibition of the enzymes of the P₄₅₀ pathway may thus lead to areduction in drug interaction.

1. A method of treating a subject that is undergoing methylphenidatetherapy and concomitant therapy with another drug, wherein said therapyis for attention-deficit hyperactivity disorder and said method providesfor reduced side effects or reduced potential for abuse relative toracemic methylphenidate, said method comprising administering aneffective amount of d-threo-methylphenidate to said subject daily. 2.The method according to claim 1, wherein said d-threo-methylphenidateand said another drug is formulated for administration to an adultpatient.
 3. The method according to claim 1, wherein the dosage ofd-threo-methylphenidate administered to said subject is 5 mg to 60 mg.4. The method according to claim 1, wherein said d-threo-methylphenidateis in at least 95% enantiomeric excess relative tol-threo-methylphenidate.
 5. A method for treating a patient having acondition susceptible to treatment with methylphenidate and alsoexhibiting or likely to exhibit other central nervous system disorders,wherein said condition is attention-deficit disorder orattention-deficit hyperactivity disorder and said method provides forreduced side effects or reduced potential for abuse relative to racemicmethylphenidate, said method comprising administering an effectiveamount of d-threo-methylphenidate to said patient daily.
 6. The methodaccording to claim 5, wherein the dosage of d-threo-methylphenidateadministered to said patient is 5 mg to 60 mg.
 7. The method accordingto claim 5, wherein said d-threo-methylphenidate is in at least 95%enantiomeric excess relative to l-threo-methylphenidate.
 8. A method fortreating a patient having a condition that is susceptible to treatmentwith methylphenidate and concomitant therapy with another drug, whereinsaid condition is attention-deficit disorder or attention-deficithyperactivity disorder and said method provides for reduced side effectsor reduced potential for abuse relative to racemic methylphenidate, saidmethod comprising administering an effective amount ofd-threo-methylphenidate to said patient daily.
 9. The method accordingto claim 8, wherein the dosage of d-threo-methylphenidate administeredto said patient is 5 mg to 60 mg.
 10. The method according to claim 8,wherein said d-threo-methylphenidate is in at least 95% eneantiomericexcess relative to --threo-methylphenidate.